Abstract

Persistent infections involving high-risk types 16 and 18 of Human Papillomavirus (HPV) have been established as the etiological agent of cervical cancer. Recent data indicate that several polymorphisms of key regulators from the DNA damage repair pathways are associated with cancer development susceptibility. The long arm of chromosome 11 has received much attention as a high frequency of epigenetic deletions of various sites, observed in HPV-long term infection that lead to cervical cancer, indicating the presence of putative tumor suppressor genes and its association with disease progression. To better understand the importance of chromosome 11q22-23 region in the development of cervical cancer, we investigated genetic and epigenetic alterations of the tumor suppressor ATM gene in human keratinocytes transfected with HPV E6/E7 oncoproteins (16-MT). In the present study we examined 16-MT cells for epigenetic changes and chromosome imbalances, using FISH, and arrayCGH. We used several FISH probes, mapping to region 11q22-23 where the ATM gene is located. Our study revealed that the ATM gene located on chromosome 11q is deleted, relating to chromosome deletions, that are recurrent abnormalities in cervical cancer, implicating the loss of tumor suppressor genes as a significant mechanism that drive cells to become cancerous. This study was designed to investigate genetic instability using HPV16 E6/E7 oncoproteins to better understand the importance of chromosome 11q epigenetic changes. Deletion of 11q22-23 was observed in all metaphases scored. With restricted areas of deletions, two chromosomal regions of possible importance in cervical carcinomas could be distinguished. The first region is D11S1325 and the second region is D11S2179. The second region may contain part of the ATM gene. The results indicate that a tumor suppressor gene on chromosome 11q22-23 may be involved in the carcinogenesis of the cervix and the involvement of the ATM gene, as the driving factor remains a possibility.